eLetters

46 e-Letters

We have a few concerns on the report by Clemson CM et al on the
efficacy of valproic acid (VPA) in 7 patients with retinitis pigmentosa
(RP) [1]. Was the time period of 6 months for using VPA the maximum time
that was allowed by the institutional review boards? The degree to which
the retina was affected by RP was not mentioned in each case (either in
the form of photographic evidence or by electro...

We have a few concerns on the report by Clemson CM et al on the
efficacy of valproic acid (VPA) in 7 patients with retinitis pigmentosa
(RP) [1]. Was the time period of 6 months for using VPA the maximum time
that was allowed by the institutional review boards? The degree to which
the retina was affected by RP was not mentioned in each case (either in
the form of photographic evidence or by electrophysiological studies). Age
-matched appropriate controls need to be incorporated in future studies as
younger retinas or retinas lesser affected by RP usually respond better to
treatment [2]. Conversion of vision from Snellens acuity chart into logMAR
has a risk of wrongly estimating visual acuity given the inherent pitfalls
of the Snellens acuity test [3]. Therefore to extrapolate and show
improvement in the mean of visual field and visual acuity is
inappropriate. The authors did not report the number of visual field
plots that were done pre-treatment (except patient 5), as an improvement
in visual field in patients could be an improvement in the learning curve
and not a real improvement in visual field.

Although this paper calls for a well-designed prospective case-
control study, it does provide proof-of-concept that valproic acid may
have retinal neuroprotective effects as observed in animal models [4, 5].
VPA offers neuroprotection and neuroregeneration in a histone-acetylation-
independent manner, more likely involving the Wnt (wingless-type MMTV
integration site family)/beta-catenin signalling pathway [5]. Sustained
Wnt2b expression helped maintain undifferentiated retinal stem cells in
the ciliary marginal zone, promoted proliferation of retinal stem cells in
vitro, including regeneration of rhodopsin-positive photoreceptor cells in
the RP mouse model. VPA and related HDAC inhibitors could potentially be
valuable drugs for patients with retinal degenerative disorders and should
not be discounted without good evidence to the contrary.

Conflict of Interest:

Dear Editor, we thank West et al. for their interest in our paper.
Firstly, we wish to point out that as stated in our paper's conclusion, we
fully endorse early surgery in all cases of paediatric & adolescent
blowout fracture. We are committed to educating referrers and colleagues
in other specialities to recognize & refer these patients as soon as
possible. Secondly, West et al claim that we did not adequatel...

Dear Editor, we thank West et al. for their interest in our paper.
Firstly, we wish to point out that as stated in our paper's conclusion, we
fully endorse early surgery in all cases of paediatric & adolescent
blowout fracture. We are committed to educating referrers and colleagues
in other specialities to recognize & refer these patients as soon as
possible. Secondly, West et al claim that we did not adequately highlight
patients with white-eyed blowout fractures who they presume have muscle
ischaemia and poorer outcomes. Jordan et al's paper on white-eyed blowout
fractures postulated that perimuscular soft tissue entrapment causes
muscle ischaemia due to a "compartment-type syndrome"1. This remains
unproven. Iliff et al's clinical and experimental animal study could not
confirm the existence of orbital compartment syndromes in blowout
fractures2. They identified direct muscle damage, nerve contusion and
incarceration of the muscular fascial network as more likely causes of
postoperative diplopia. If muscle ischaemia was present, urgent surgery
(within hours) to prevent muscle necrosis would be indicated. Other
causes of muscle damage may not require the same degree of urgency.
Further information on the causes of diplopia and prospective randomized
trials comparing outcomes after various intervals to surgery are required.
Until more is known, our stance on white-eyed blowout fractures is not
dogmatic: each case is considered individually and surgery is performed as
soon as practicable. This approach does not preclude urgent surgery if it
is required.

West et al. also stated that our results may have been better if our
patients with white-eyed blowout fractures had undergone earlier surgery.
They compared our results with three studies 3-5. Unfortunately, each
study presents its results differently. We described diplopia on extreme
gaze as self-reported or elicited on examination. We consider these
children did not have significant diplopia. Ethanadan et al describe a
similar group with diplopia as not "relevant" for day to day activites3.
Gerbino et al describe three motility outcomes: full extraocular muscle
recovery, diplopia in supraduction & vertical diplopia4. They did not
state if postoperative diplopia in their cases was functionally
significant or elicited on examination only. Bansagi et al used a
numerical scale for comparing supraductions before and after surgery
instead of reporting on diplopia5. Comparison of our results and those of
other studies is difficult. We do not accept that our results are
necessarily inferior to other studies' results when consensus on
describing motility outcomes is lacking.

Newsham's recent article on the management of amblyopia is timely but
misdirected.
Illusions concerning occlusion therapy are repeated with tourettic
persistence despite a lack of supporting objective scientific evidence.
(Gregson R. Why are we so bad at treating amblyopia. Eye 2002;16:461-2)

Reports of effective treatment are diminished by the number of
subjects who decide to discontinue treatment. Of those who continue
treatment approximately 20 percent, particularly those with initial acuity
less than 20/125, fail to improve. Of those who do improve by three or
more lines on a Snellen chart, which may still leave them unable to read
or perform other important tasks, (Stifter E, Burggasser G, Hirmann E,
Thaler A,et al. Monocular and binocular reading performance in children
with microstrabismic amblyopia. Br J Ophthalmol. 2005;89:1324-9.) about
half will regress to initial levels after discontinuation of patching.
Assessing the usefulness of this therapy is limited by a lack of untreated
controls, failure to consider the placebo effect, and improvement due to
increasing literacy, age, and familiarity with the tests. A myriad of
treatment protocols including acupuncture, drugs, tinted lenses,
exercises, sewing eyelids, refractive surgery, and many other remedies
have comparable outcomes. "The diversity of treatment protocols
accentuates another dilemma owing to our paucity of knowledge on the dose-
effect relation - a situation one finds hard to imagine for any comparably
established therapy outside ophthalmology. In other words we have no
understanding of the dose-effect relation of occlusion in amblyopia
therapy." (Simonsz HJ, et al. Electronic monitoring of treatment
compliance in patching for amblyopia. Strabismus 1999 ;7:113-23.)

The traditional concepts of the etiology of amblyopia were developed
before the availability of means for axial length measurement, MRI's, or
magnification corrected retinal photography. Recent studies, notably
(Pineles SL, Demer JL. Bilateral abnormalities of optic nerve size and
eye shape in unilateral amblyopia. Am J Ophthalmol 2009;148:551-7 and
Lempert P. Retinal area and optic disc rim area in amblyopic, fellow, and
normal hyperopic eyes: A hypothesis for decreased acuity in amblyopia.
Ophthalmology 2008;115:2259-61) indicate that the presumably amblyopic
eyes have optic nerve hypoplasia as well as additional structural defects.
Other reports demonstrate that both eyes are have impaired function of
different severity and anatomy which indicates that amblyopia really a
binocular disorder.

Redirecting attention to prenatal conditions that are associated with
optic nerve hypoplasia is likely to be more effective than continued
adherence to traditional therapies in preventing vision impairment in
children.

Dear Editor,
We appreciate the concerns raised by Sandberg et al. in their recent
letter1 pertaining to the design and statistical methods of our analysis
described in our recent article,2 and we welcome the opportunity to
respond to each point raised.

Study Design. We agree that ideally the best, "gold standard" study
design would involve the use of matched controls, with matching on eye
function at baseline, as we plan to do in our upcoming clinical trial. For
preliminary pilot studies, however, other study designs, including
methodologies that do not have controls, can also be meaningful,
especially when the objectives are to assess treatment potential and
establish the equipoise necessary for further investigation in a
randomized control study. An example that is relevant to our work is
presented by an article from one of the authors of the letter (Rosner et
al., 2006; Section 4.1),3 in which the investigators assessed the
potential benefit of treatment and concluded that their findings were
suggestive of a lack of effect due to treatment. These researchers did not
have a control group, yet they felt comfortable with the conclusions based
on this design. Our analytical design and findings are consistent with
this example. Our focus was an exploration of potential therapeutic value,
and our detailed description of visual function in 14 eyes establishes a
possible treatment benefit that merits a randomized control trial.

Statistical analysis. We believe that the exploration of treatment
potential in a sample size of seven is best addressed with detailed
descriptions rather than formal tests of statistical significance. Given
that significance levels were reported, however, we agree with Sandberg et
al. that the unit of analysis should have taken into account the
correlation structure of the data. We thank Dr. Rosner for pointing out
the modification of the Wilcoxon Signed Rank Test for use with paired
data. We expect to use this modification in future studies that have
formal tests of significance as their goal. With respect to our pilot
analysis, with this correction, calculated by Dr. Rosner, the statistical
significance of the improvements in visual field and visual acuity (p=
0.14 and p=0.06, respectively) no longer meets widely used thresholds
(such as p < 0.05), as the Sandberg et al. letter points out. We reason
that these p-values, as they pertain to a small sample size setting, do
not provide conclusive evidence of the null hypothesis, as the associated
confidence intervals of the differences are wide. Accordingly, while we
could calculate a corrected analysis of statistical significance, we
believe the relevance of our findings to the advancement of treatment for
retinitis pigmentosa would be the same. We would also like to note that
the calculated p-values for improvement in visual acuity and visual field
have been compared to a hypothesis for no change in function. We would
expect a comparison to historical controls that experience on average some
deterioration in function to have associated p-values that are closer to p
<0.05. We observed a potential for treatment benefit that was
accompanied by at most modest and tolerable side effects. This is of
public health importance as our data contribute to a growing body of
literature that collectively suggests the appropriateness of a larger
scale study of valproic acid therapy that utilizes randomization and
comparisons with controls.

Floor effects. We appreciate the issue of floor effects. In this
regard, we wish to note that in our sample, only 1 of the 14 eyes studied
exhibited visual acuity of less than 20/200 (logMAR = 1.0). Importantly,
even in this case, the visual acuity is only questionably "floor". Visual
acuity below 20/200 is routinely measured in clinical settings and when
converted to logMAR values, it can be recorded reproducibly to a logMAR of
2.6. Additionally, only 1 out of 14 eyes had a visual field area at
baseline, which was < 10% of normal. Thus, only this one eye could be
considered for some presence of floor effect. However, even in this case,
the increase in visual field area from baseline to follow-up was
relatively large (from ~4% to ~10% of normal), so it is unlikely that such
an increase happened by chance only. In summary, we feel that floor effect
concerns are unjustified in this particular data set.

Comparison with historical data. We understand that one of the goals
of relatively large observational studies like the ones cited in our
work4,5 is to serve as benchmarks against which subsequent (often much
smaller in size) studies can be compared. Of note, testing of the visual
field in our work was done exactly the same way as in the two cited works.
Also, the population can be regarded as very similar, as in all three
cases the patients were referred to a large tertiary center. In this
regard, the criticism that we used "different methods" is unjustified.
Again, we wish to reiterate that ours was an exploratory analysis that
included a comparison of our findings with those of other, independent
studies. The utility of our analysis, as with other small-scale studies,
is to inform the appropriateness and design of future, large-scale
studies. Indeed, we fully support the concept that large-scale clinical
trials that enroll a broad diversity of patients are the best tools for
inference to a "whole" population.

Relevance to a clinical trial. Retinitis pigmentosa is a very
serious disease, there is currently no treatment, and it is devastating
for its sufferers. In our opinion, our detailed description of the seven
patients' longitudinal data regarding their responses to valproic acid
administration is essential to the understanding of its therapeutic
potential. Eleven of the 14 eyes (79%) presented in our analysis
experienced gains in retinal function, and the probability of this
happening by chance is small, even when corrected for clustering, etc. Our
conclusion is that these results, together with the findings of similarly
conducted independent studies, make a clear case for further study using
randomized control trial methodology. We would like to also point out that
regarding the lack of a large sample size in our pilot analysis, we are in
a similar situation as Dr. Berson and his group faced before the
initiation of their clinical trial testing the effects of vitamin A in
retinitis pigmentosa in 1984, when the preliminary clinical data were
limited to the finding that ERG was lower in 2 out of 18 patients on
Vitamin A (11%, no statistical significance presented),6 yet the trial
proceeded and established no effect on visual field or visual acuity, but
confirmed a small positive effect on ERG (which was the primary endpoint)
due to treatment.

Valproic acid side effects. First, our article included the side
effects that were reported to us by the patients whose charts we analyzed,
as is essential in an exploratory pilot analysis. Second, the Sandberg et
al. letter introduces isolated anecdotal evidence regarding valproic acid
treatment side effects. Virtually every drug is associated with a myriad
of mostly rare side effects that are bound to occur when administered to
the general population. However, the correct approach would be to place
potential side effects into the context of the drug's potential
therapeutic benefits. With respect to valproic acid, this drug was in
clinical use in Europe since the mid-1960s, was approved in the United
States in 1978 and has met the test of decades of use in the general
population. Thus, its side effects are well known. Specifically, it has
been clearly established that the frequency and severity of most of the
side effects of valproic acid are dose-dependent. The maximum recommended
dose in the US is 60 mg/kg/day? (which translates to 4500 mg/day for a 75
kg patient), and this is the dose range where the most (and most severe)
side effects appear. In the present analysis, the maximum dose used was
~10 mg/kg/day, which is six times less than the maximum recommended dose.
It has been demonstrated that the lower dosing level used in our work is
associated with very low frequency and low-grade severity of side effects.
Examining the literature reveals that in a study summarizing results of 16
trials and 1140 patients treated with different doses of valproate, side
effects were observed in 26% of the patients, but discontinuation of the
therapy was required in only 2%.7 Furthermore, in 48 children dosed with
30 mg/kg/day or more of sodium valproate for 22 months, a change in
therapy was required in five patients (average dose = ~47 mg/kg/day) and
withdrawal was required in two patients (average dose = ~43 mg/kg /day).8
Similarly, in a study that followed up 118 patients for an average period
of 18 months on valproate monotherapy on a mean dosage of ~19.4 mg/kg/day,
only four patients (3.4%) elected to discontinue treatment.9 Side effects
in this last study were observed in 16% of the patients at the time of the
first follow-up visit, but only in 2% (excluding weight gain that had
stabilized) by the last analyzed follow-up visit.9 Neither hearing loss
nor deterioration in vision function was reported in any of the three
studies cited above (a combined population of 1306 patients) and,
therefore, if associated with the drug intake, should be a very rare
occurrence. As mentioned in our article and in our recent letter to the
journal,10 we saw very few side effects with the low dose employed in our
analysis, and only one patient elected to discontinue treatment. We agree
with a recent review that summarized the 30 years of clinical experience
with the drug, which stated "Valproate also possesses an impressive safety
profile, being well-tolerated in most patients".11

Summary. Although valproic acid has been used for several indications
during the past 30+ years, its possible therapeutic effect in retinal
degenerative diseases is currently unknown. We believe that the state of
knowledge regarding the treatment of retinitis pigmentosa at the inception
of our analysis warranted a "pilot analysis" approach to the exploration
of valproic acid and a detailed description of individual eyes. We would
like to emphasize that the goal of our pilot data analysis was to examine
the potential benefit of valproic acid; this analysis provided preliminary
data that we believe warrants further investigation in a randomized
control study. The initial impression of a therapeutic benefit presented
in our analysis can be best clarified in such a clinical trial.12

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The Corresponding Author has the right to grant on behalf of all
authors and does grant on behalf of all authors, an exclusive licence on a
worldwide basis to the BMJ Publishing Group Ltd and its Licensees to
permit this article (if accepted) to be published in BJO editions and any
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licence.

The investigators should have performed a case-control study,
comparing patients taking valproic acid to control patients matched for
baseline field and acuity. This would have allowed for possible floor
effects due to the low baseline function of some of the treated patients
(i.e., who might be more likely to improve rather than decline over follow
-up by chance variability) and avoided their use of historical rates of
change drawn from different populations tested by others with different
methods.

Statistical analyses should have been performed on patients, instead
of eyes, unless controlling for the intraclass correlation between fellow
eyes of the same patient. A reanalysis of their results by the signed-rank
test for cluster-correlated data1 reveals weaker effects for visual field
improvement (e.g., p = 0.14 versus no change) and visual acuity
improvement (e.g., p = 0.06 versus no change) in their cohort. In fact,
none of the presented comparisons was statistically significant with this
test.

The authors did not cite published side effects of valproic acid
(e.g., constipation, diarrhea, and hearing loss). Among patients given
valproic acid elsewhere, one reported to us a further impairment of
hearing and no visual improvement after taking this drug for several
weeks. Another showed decline in retinal function while on this drug for
one year.

We believe that the above-named report does not provide a scientific
rationale for the clinical trial that the authors recommend.

Conflict of Interest:

Ryan and Margrain's letter highlights some key findings from a report
they conducted on behalf of the Thomas Pocklington Trust. 1 They found
that there are many people in Wales requiring visual rehabilitation who do
not meet the current criteria for certification as visually impaired.
They found also that there had been poor uptake in Wales of systems which
were designed to support those who need aid who do not meet such...

Ryan and Margrain's letter highlights some key findings from a report
they conducted on behalf of the Thomas Pocklington Trust. 1 They found
that there are many people in Wales requiring visual rehabilitation who do
not meet the current criteria for certification as visually impaired.
They found also that there had been poor uptake in Wales of systems which
were designed to support those who need aid who do not meet such
guidelines (the LVL and the RVI). These are important findings that need
airing and discussion, but are they really findings that should call into
question the value of a system that has facilitated support to visually
impaired individuals in need since 1920? This is implied by the title
which is perhaps misleading and does not reflect the content of the
letter. It should be noted that this study also reported that just under
14 % of those with registrable visual acuities were not registered and
were not known to social services. These data are in line with those
reported by Tate et al in a report commissioned by the RNIB which
estimated that 89 % of people over 75 years of age who were eligible for
registration were indeed registered.

Conflict of Interest:

As a research group with no commercial interest in any macular
pigment optical density (MPOD) measurement devices, or nutritional
supplements, we feel that we were well-placed to carry out this
independent clinical assessment of the reliability of MPS 9000. Our study
was prompted by the fact that we could find no reported coefficient of
repeatability value within the literature, and none was provided by the
manufacturer...

As a research group with no commercial interest in any macular
pigment optical density (MPOD) measurement devices, or nutritional
supplements, we feel that we were well-placed to carry out this
independent clinical assessment of the reliability of MPS 9000. Our study
was prompted by the fact that we could find no reported coefficient of
repeatability value within the literature, and none was provided by the
manufacturer. We had planned to use this instrument in our own research
studies investigating the impact of nutritional supplementation on MPOD.
For this purpose, we needed to know the level of MPOD change that could be
considered clinically significant. We felt that this information would
also be useful to other clinicians who had already purchased the
instrument, or were thinking of doing so.

In our study MPOD measurements were obtained as per the manufacturer
guidelines (MPOD Reference Guide and Technician Training). We were careful
to follow these instructions in the same way as a clinician would in
practice, as our aim was to assess the reliability of the MPS 9000 in a
clinical environment. Dr Murray and colleagues have provided a coefficient
of repeatability value in their letter. However, we would suggest that
this low value has been achieved by using data screening methods that are
not discussed in the operation manual that we were provided with. As such,
this may not be a true reflection of the level of repeatability that would
be achieved in ophthalmological or optometric practice, but may be more
applicable to researchers working in this area.

We do not consider the reference that Dr Murray and colleagues make
to the correlation between the MPS 9000 and other methods of MPOD
measurement to be relevant. This is not what we set out to assess; we
wanted to analyse the level of noise within MPOD measurements using the
MPS 9000. To illustrate this point, we carried out correlation analysis on
our repeat readings and found that for all four comparisons the
relationship between the two data sets was highly significant
(p<0.001). The variability between the two data sets ranges from 3-
15%. The important point here is that there may be little variability
between two data sets, and the two data sets may also be significantly
correlated, but this does not mean that there is no instrument noise. The
clinically significant change in MPOD over time could only be determined
by calculating the coefficient of repeatability.

The reference that Dr Murray and colleagues make to the measurement
of repeatability reported by van der Veen in 2009 is also irrelevant, as
this group reported a correlation coefficient, mean test-retest
variability, and a percentage value calculated by dividing the mean of the
differences by the mean value of the two estimates. None of these values
can be directly compared with our coefficient of repeatability.

Conflict of Interest:

Dear editor,
I read with interest Catederal et alÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÂ¢Ã¢ÃÂ¢s study on the use of polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis in donor corneal tissues.1 The authors report the presence of M. tuberculosis DNA in donor corneas of patients with no documented history of tuberculosis. However there are several methodological erro...

Dear editor,
I read with interest Catederal et alÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÂ¢Ã¢ÃÂ¢s study on the use of polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis in donor corneal tissues.1 The authors report the presence of M. tuberculosis DNA in donor corneas of patients with no documented history of tuberculosis. However there are several methodological errors in the study which need to be discussed. The most significant flaw is the lack of biological plausibility for the presence of M. tuberculosis in the corneal tissue, which is not known to contain any phagocytic cells, except probably at the limbus. The authors have not mentioned the size of the donor corneal button or the degree of corneal vascularization at the limbus. A large corneal button or presence of significant corneal vascularization could account for the detection of mycobacterial DNA in corneal tissue. Besides, the possibility of ÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÃ contaminationÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÂ¢Ã¢ÃÂ¢ of the corneal surface by the aqueous cannot be ruled out.
Even then, the high incidence of M. tuberculosis DNA in ÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÃ TB-negativeÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÂ¢Ã¢ÃÂ¢ eyes remains unexplained. The authors make a passing reference to the use of positive and negative controls during each amplification reaction, but the nature of these controls or the outcomes after amplification are not mentioned. Did the authors get accurate results with each of the controls? The basis for selection of non-TB donors is also vague as the authors have pointed out themselves. Finally, the authors refer to the low incidence of ocular tuberculosis (1-2%) in patients with pulmonary tuberculosis. However, it is well known that ocular tuberculosis is very rarely seen in patients with systemic tuberculosis.2 Hence the overall incidence of ocular tuberculosis ÃÃÂ¢ÃÂ¢Ã¢ÃÂ¬ÃÂ¢Ã¢Â¬Ã  isolated, as well as in association with systemic tuberculosis, needs to be mentioned. To summarize, the issues highlighted by this study need to reviewed in light of the methodological errors and lack of biological plausibility.
Soumyava Basu
References:
1. Catedral EJ, Santos RE, Padilla MD, Fajardo-Ang C. Detection of Mycobacterium tuberculosis in corneas from donors with active tuberculosis disease through polymerase chain reaction and culture. Br J Ophthalmol. 2010;94:894-7
2. Donahue HC. Ophthalmologic experience in a tuberculosis sanatorium. Am J Ophthalmol. 1967;64:742-8

Conflict of Interest:

We appreciate the interest of Van Schooneveld et al.1 in our recent
BJO article.2 Our small, retrospective chart review of RP patients treated
off-label with valproic acid is only the first step in the process of
understanding the potential utility of the drug for patients with this
sight-threatening condition, for which there are no current therapeutic
options.

We appreciate the interest of Van Schooneveld et al.1 in our recent
BJO article.2 Our small, retrospective chart review of RP patients treated
off-label with valproic acid is only the first step in the process of
understanding the potential utility of the drug for patients with this
sight-threatening condition, for which there are no current therapeutic
options.

The size and the scope of our article was limited by the nature of a
retrospective chart review, which only allows analysis of follow-up that
occurred within the defined time frame. Additional factors limiting the
scope and length of the study included (1) the logistical and financial
complexity involved in following up patients in two geographically
separated states; (2) the differences in available equipment in the two
institutions; and (3) the importance of sharing a potential new treatment
with the ophthalmic community sooner rather than later.

The retrospective chart review process was begun while the senior
author was at the University of Florida, and because he moved from Florida
to Massachusetts, the analysis was carried out in Massachusetts and
appropriate Institutional Review Board approval from the Massachusetts
site was published in the article.

The valproic acid treatment regimen analyzed retrospectively in the
charts of the seven patients is detailed in the article. Prospective
follow-up was not done, nor is it allowed under the mandate of a
retrospective chart review. To clarify, the treatment of patients with
valproic acid has not been stopped for any of the patients who tolerated
it well (most of the patients). Our retrospective chart review reported on
in the BJO article captured a relatively short period for a slowly
progressive condition like RP, and we recognize that the most rigorous
validation of a therapy will be a well-designed clinical trial. A
prospective, multicenter, randomized, placebo-controlled clinical trial is
in the final stages of preparation3 in the U.S., and we will be
registering this clinical trial very soon at the U.S. clinical trials
website, www.clinicaltrials.gov.

On a separate note, as part of our current clinical practice in
Massachusetts, several RP patients new to our practice have been treated
with valproic acid; our clinical impressions of these new patients are
similar to what was reported in our article.

There is mounting evidence that valproic acid may have potent
neuroprotective properties and have other beneficial effects,4-6 and we
have intensive in vitro and in vivo experiments (including mice models of
RP) underway. The results of our experiments in the context of retinal
degenerative conditions have been reported at recent meetings.7-11 We are
planning to submit these data as articles to peer-reviewed journals.

Our work has been motivated by the spirit of translational research,
with the goal of more quickly identifying a promising therapeutic approach
and stimulating scientific interest and further research, based on
preclinical data and unexpectedly positive vision function observed in a
clinical setting. Repurposing drugs such as valproic acid, which have been
shown to be safe, is an economical and time-efficient way to bring new
treatments to patients.

Conflict of Interest:

Dear Sir,
With great interest we read the article of Clemson et al. about a new
treatment for retinitis pigmentosa (RP). However, the authors' claim that
their data suggest that valproic acid (VPA) may be an effective treatment
for RP is unfounded and also regrettably misleading for the many desperate
RP-patients. In fact, we are surprised that the editors of the BJO have
published this study in its present form.
Firstly,...

Dear Sir,
With great interest we read the article of Clemson et al. about a new
treatment for retinitis pigmentosa (RP). However, the authors' claim that
their data suggest that valproic acid (VPA) may be an effective treatment
for RP is unfounded and also regrettably misleading for the many desperate
RP-patients. In fact, we are surprised that the editors of the BJO have
published this study in its present form.
Firstly, the design of the study as well as the medical ethical approval
(approved in Massachusetts, but conducted in Florida) is obscure: why were
the patients treated only for a very short time (2 to 6 months), while RP
is a slowly progressive chronic condition? Why were only 7 patients
treated and described as the results were as promising as the authors
claimed? Why was the treatment stopped, as there were no or few side
effects and what happened after the treatment was stopped?
Secondly, the theoretical action of VPA on the dysfunctional
photoreceptors is unsatisfactorily explained and no experimental data on
retinal tissue are provided. Why was the treatment not tested on rats or
mice with RP? In view of the limited life span of these animals,
unequivocal data on the efficacy of VPA could have been provided.
Thirdly, the authors announce their intention to start a controlled
clinical trial with VPA, but no such trial has been registered yet at the
Current Controlled Trials Register. For the RP-patients longing for
treatment, this is very disappointing, to say the least.